640
Journal of the American Chemical Society
101:3
/
January 31, 1979
Reactivity of Superoxide Ion with Carbonyl Compounds in Aprotic Solvents Morton J. Gibian," Donald T. Sawyer," Timothy Ungermann, R. Tangpoonpholvivat, and Mark M. Morrison Contribution from the Department of Chemistry, University of California, Riverside, California 92521. Received June 26, 1978
Abstract: Benzaldehyde and ketones undergo no net elementary reaction with superoxide ion (02-e) in inert solvents such as pyridine, toluene, and benzene. Esters, however, are hydrolyzed via an initial reversible nucleophilic addition of 0 2 - - to the carbonyl carbon followed by loss of alkoxide from the tetrahedral intermediate (rather than its reduction). This pathway is strongly supported by the relative second-order rate constants for the reaction of Ol-. in pyridine with ethyl acetate (1) and phenyl acetate ( lo4) together with results earlier reported in the literature. For the ketones and benzaldehyde, reversible initial addition of 0 2 - * to the carbonyl must occur as well, but the absence of a viable leaving group precludes a net reaction. The decomposition products of 0 2 - - are highly reactive with benzaldehyde, apparently through a base-catalyzed process. These alkaline decomposition products also are reactive toward acetonitrile. The products and mechanisms for the reactions of 0 2 - . and its decomposition products in these systems are discussed.
Introduction The reactivity of superoxide ion, 02--, with organic molecules has been the subject of considerable recent interest for two reasons. The discovery and subsequent elaboration of the fact that superoxide is generated ubiquitously in aerobic organisms made it biochemically important to understand the chemical reactivity of 0 2 - s . Furthermore, because a "new" species is in hand, this simple ion represents an opportunity to examine and broaden our understanding of elementary reactivity patterns from a purely fundamental chemical view. Stimulants to such studies have been the development of electrochemical to generate pure, stable solutions of 0 2 - e and the somewhat later development of the crown-ether solubilization of KO2 in organic s o l v e n t ~ , ~again - l ~ to give relatively stable solutions of 0 2 - ~ . ~ ' Both methods of 0 2 - - generation (electrochemical and crown ether/K02) have been used here to study the reactivity of 0 2 - . toward organic compounds; in particular a functional group survey approach has been adopted. As reported recently,12 we have found that while compounds with certain organic functional groups react to give observable products, examination of the 0 2 - - decay (electrochemically) reveals the absence of an increased rate of 0 2 - . loss, above the usual slow autodisproportionation, for these substrates. Close examination of several of the systems has led us to conclude that much of the chemistry that has been obsermed is due not to reections of 0 2 - - with the organics, but to reactions of the decomposition products of Oz-. after its disproportionation. W e report here on the reactivities of simple aldehydes, ketones, and esters in pyridine, toluene, and benzene (inert solvents). Some interesting chemistry of the KO2-crown ether system with benzaldehyde in acetonitrile is also revealed. Acetonitrile is apparently inert to superoxide itself, but is highly reactive to the basic decomposition products of 0 2 - e . Several previous workers have included aromatic aldehydes in their studies, and concluded that 0 2 - - oxidizes benzaldehyde to either benzoic acid or perbenzoic In inert solvents this is indeed what we observe after long reaction times, but the chemistry along the way is complex and interesting. Aliphatic aldehydes give complicated product mixtures. Est e r ~ , ~as~ previously ,'~ assumed, do undergo elementary reactions with superoxide. On the basis of product and kinetic data (along with appropriate controls), a reasonable picture of the elementary chemistry of 0 2 - . with the carbonyl functionality can be presented. 0002-7863/79/1501-0640$01 .OO/O
Experimental Section Materials. Solvents other than acetonitrile and pyridine were reagent grade and dried over molecular sieve. Acetonitrile and pyridine were Burdick and Jackson high-purity solvents (H20,0.009%) which were used as received. (Further purification attempts with these materials resulted in no improvement in purity. Gas chromatographic and electrochemical analysis confirmed the extremely low water contents specified by the supplier.) KO2 was from Alfa Inorganics (96.5%), and all other inorganics were Mallinckrodt A R grade. Benzyl alcohol was Baker AR, distilled. Benzaldehyde was Aldrich reagent, and was distilled immediately before each use through a 3-ft glass helices packed column under vacuum with a n argon bleed. The material was kept rigorously anaerobic a t all times. 18-Crown-6 ether was synthesized according to a literature procedure,]8dried, and stored in a vacuum desiccator. All other organics were from Aldrich, reagent grade, except for m-chloroperbenzoic acid, which was technical grade (85%). Methods. KO2 Experiments. In a typical experiment, KO2 (finely ground in a dry N2 atmosphere glovebag) and crown ether were weighed in the glovebag. These materials were added to a roundbottom flask (already containing solvent and a stirring bar) fitted with a serum cap, an inlet N 2 bubbler, and a CaC12 drying tube with serum cap and exit needle. The vessel for small-scale runs was a small vial with a fresh serum cap fitted with A r inlet and outlet needles. The organic substrate (benzaldehyde or other reagent) was then injected into the vessel. During the additions and the reaction the solution was continuously bubbled with nitrogen and magnetically stirred as rapidly as feasible. In some runs, the organic reagent was added before the KO2 and a sample removed for analysis prior to initiation of the reaction. In most runs, the reaction mixture was analyzed several times during the reaction. Small samples were withdrawn through the serum cap and either injected directly into the gas chromatograph, or neutralized and then analyzed. Finally, the total mixture was added to aqueous acid and the products were isolated by extraction and recrystallization. Runs with salts other than KO2 were handled identically. The gas chromatography involved a dual column analysis on Carbowax 20M a t 135 "C for reactions in pyridine. Acetonitrile reactions were analyzed on SE-30. Mass spectra, N M R , I R , and melting point determinations as well as comparison of G C retention times to those of known compounds were used to identify products indicated. C6H5COCH2CN (mp 78-80 "C, lit. 81-82 "C)I9 had I R (cm-I) 1700 (C=O), 2270 (C=N), and 3000 (Ar-H); N M R F 7.3-8.1 (m, ArH) and 4.14 (s, CH2); mass spectrum m/e 145 (P), 105 (C6H$O), 77 (C6H5), and 40 (CHzCN), in agreement with the assigned structure. Electrochemical Measurements. Superoxide ion was generated by electrochemical reduction of 0 2 a t a gold electrode (-1.2 V vs. SCE)
0 1979 American Chemical Society
Gibian, Sawyer, et al.
/
64 1
Reactivity of Superoxide Ion with Carbonyl Compounds
Table I. Reaction of Superoxide Ion with Esters in Pyridine"
initial [ester], mM
initial initial 0 2 - - decay mM rate, fiM s-l
[02-.1,
E t OAc, 31rnM
k2,
M-I
s-l
l
........... . +OAc,l.GrnM H20,0.5rnM 4 0
T
A. Ethyl Acetate 51 51 51 16 31 104 26 50
4.70 0.34 1.10 1.10 1.20 1.10 1S O 1.30
3.00 0.16 0.63 0.21 0.39 0.73 0.74 0.84
0.012 0.009 0.01 1 0.012 0.010 0.007 0.018 0.013 av 0.01 1 Ifr 0.002
BLANK 1.20
-,
TI
\
E
\
B. Phenyl Acetateb 0.10
0.044
0.72
\ \
160 Ifr 50
0 2 - - generated by controlled-potential electrolysis of 0 2 prior to the addition of substrate. Concentrations of 0 2 - . monitored by cyclic voltammetry (see Experimental Section and Results). Difficult to measure because of its rapid rate of reaction. As measured by direct cyclic voltammetric reduction of 0 2 in the presence of substrate (Figure 2), k 2 has a value of 140 f 70 M-' s-l (see Results).
I N
0 U
o'601 0.40
in pyridine with 0.1 M tetra-n-propylammonium perchlorate. Superoxide solutions (0.8-6.0 mM) were degassed with argon to remove dissolved 0 2 prior to addition of substrate. The concentration of 0 2 - e
was monitored by linear sweep voltammetry with the anodic peak current measured at -0.7 V. Standardization of the current in relation to 0 2 - . concentration was accomplished by coulometric analysis. The electrochemical instrumentation consisted of a Princeton Applied Research Carp. Model 173A potentiostat, Model 179 digital coulometer, Model 175 Universal Programmer, and a HewlettPackard Model 7030A X-Y recorder. The three-electrode system included an Ag/AgCl (aqueous Me4NCI) cracked bead reference electrode adjusted to 0.000 V vs. SCE, a Pt flag auxiliary electrode separated from the bulk of the solution by a medium porosity fritted disk, and a gold working electrode. The reference electrode was held in a Liggin capillary to minimize iR errors in the measured potential. For cyclic voltammetry experiments a Beckman Pt disk electrode (0.23 cm2 area) was used as the working electrode. The electrolysis cell consisted of either a Leeds and Northrup polyethylene cell top with a 100-mL electrolysis beaker or a Brinkmann titration cell. Solutions were degassed with high-purity argon for 10 min prior to analysis and blanketed during analysis to exclude oxygen.
Results Electrochemical Monitoring of 0 2 - 0 Reactivity. Electroreduction of oxygen dissolved in pyridine yields stable, wellbehaved solutions of superoxide ion. In our hands this solvent yielded better stability and reproducibility for 0 2 - - and its reaction products than did acetonitrile or dimethyl sulfoxide. In the millimolar range, the half-life of 0 2 - . in pyridine is 4-1 2 h for the concentrations that have been used. Typically, in the absence of added substrate, -d[Oz-.]/dt = 0.04 y M s-l for 1.O m M 0 2 - s . The rates of reaction for various substrates with 0 2 - - have been measured in the presence of excess substrate by monitoring the concentration of 0 2 - - as a function of time with linear sweep voltammetry. All rates of reactions that are reported here have been corrected for the slow background decomposition of 0 2 - - (using 0.04 y M s-l). Benzaldehyde. Addition of impure benzaldehyde (reagent grade, as supplied) causes rapid decomposition of 0 2 - e . However, when this aromatic aldehyde is carefully purified by slow vacuum distillation under argon immediately prior to its addition to freshly prepared 0 2 - - solutions in pyridine (also under argon), the rate of decomposition of 0 2 - - does not increase beyond that in the absence of substrate. Some measured rates (at given concentrations of pure C6H5CHO) for 1.2 m M 0 2 - - are 0.12 (1.0 mM), 0.06 (2.0 mM), 0.06 (20 mM), 0.05 KM s-l (42.5 mM). W e have performed dozens of these experiments with many different samples of benzaldehyde, and
TIME, MINUTES Figure 1. Rate of disappearance of 0 2 - a in the presence of various substrates in pyridine (0.1 M tetra-n-propylammonium perchlorate).
the data given here are entirely typical. Storage of purified benzaldehyde in a flask under argon for even 1 day often resulted in increased rates with 0 2 - * (e.g., 0.12 y M s-] for quite pure material, >1 p M s-l for crudely distilled or "reagent grade" material). When freshly purified benzaldehyde is added to partially decomposed 0 2 - - solutions, an increase in the rate of 0 2 - - disappearance also is observed. A survey by cyclic voltammetric generation of 0 2 - - indicates no loss of 0 2 - - in the presence of the ketones benzophenone, cyclohexanone, acetone, or 2-butanone (all 0.1 M). Esters. Addition of ethyl acetate or phenyl acetate to 0 2 - s solutions results in reactions that are first order in 0 2 - . and first order in ester (typical runs in Figure 1, data summarized in Table I). For ethyl acetate and OZ-., k2 = 1.1 (f0.2) X loW2 M-' s-', and for phenyl acetate and 0 2 - - , k2 = 1.6 (f0.5)X lo2 M-' s-l. In each case, the reactions have been measured in the presence of excess ester to minimize the possibility of secondary processes and more complicated kinetics. In some cases, the rate of reaction with 0 2 - a also has been determined by the cyclic voltammetric reduction of 0 2 to 0 2 - in the presence of substrate. As illustrated by Figure 2, the peak current for the reoxidation of 0 2 - - decreases in the presence of phenyl acetate and provides a measure of the extent of the reaction. Comparison of the cathodic and anodic peak currents provides a measure of the pseudo-first-order rate constant.20 By use of various concentrations of 0 2 and phenyl acetate such measurements establish that the reaction is first order in 0 2 - and first order in phenyl acetate. Division of the pseudo-firstorder rate constant by the concentration of phenyl acetate gives k2, the second-order rate constant. The value of k2 for C H ~ C O ~ C is ~H 140 S f 70 M-' S-'; for C6H5C02C6H5 (also measured in this manner) the value of k2 is 5 f 3 M-I s-l. Reaction of Aldehydes by Chemical Studies. The alternative method for the study of the reactivity of 0 2 - n has been by use of KO2 that has been solubilized by 18-crown-6 ether (CE);
642
Journal of the American Chemical Society I
I
I
I 0.00
I
I - I 00
V v s SCE Figure 2. Cyclic voltammograms for (A) 0 2 at 1 atm (4.2 mM) and (B) 0 2 at 1 atm in the presence of 7.9 mM phenyl acetate in a pyridine (0.1 M tetra-n-propylammonium perchlorate) solvent system a t a platinum electrode (area 0.23 cm2). Scan rate, 0.1 V s-'
such an approach is necessary for efficient product studies because the concentrations of 0 2 - - from electrochemical generation are too small M). Examination of a range of solvents indicates that both dimethyl sulfoxide and acetonitrile become involved in the reaction. While the former solvent gave rather intractable products, the acetonitrile reaction products were identified and semiquantitated. The chemistry is rather interesting, and is discussed below. Acetaldehyde in dimethyl sulfoxide reacts to yield a tar, but no observable volatile product. Presumably, an aldol-type oligomerization or polymerization occurs, perhaps with incursion of solvent. Benzaldehyde in Pyridine. Because benzaldehyde cannot give aldol-type chemistry our studies have centered on this molecule. Early investigations by gas chromatography revealed that benzyl alcohol is the only observable volatile product of the K02/CE/C6H5CHO system in pyridine. With the ratio of these reactants a t 2.0/0.1/1 .O, respectively (0.07 M in CE), the initial rate of benzyl alcohol formation has been found to be close to one-half the initial rate of benzaldehyde disappearance. Workup of the reaction mixture yields benzoic acid in varying, but always major, amounts. If allowed to stir for 2 days, the reaction mixture (excess KO2) gives a 95% yield of purified benzoic acid. This brought to mind the Cannizzaro reaction, which indeed does occur a t a rapid rate (tl12 F= 0.3 2C6H5CHO
+ OH-
-
CsH5C02- -I-C6HjCH20H
h) in pyridine with KOH/CE/C6H$HO (2/0.1/1.0; C E was 0.07 M) to give the expected products. Neither K2CO3 nor H202 reacts with benzaldehyde under the reaction conditions. The reaction of m-chloroperbenzoic acid with benzaldehyde in the presence of K2CO3 and C E proceeds rapidly (as monitored by aldehyde loss), presumably to give benzoic acid.21 Benzyl alcohol reacts with K02/CE at about '/3 the rate that does benzaldehyde. The product of this reaction is benzaldehyde. When K 0 2 / C E is allowed to stand in pyridine for 3 h followed by addition of benzyl alcohol, the alcohol is oxidized a t a fivefold higher initial rate than when it is added a t the same time as all the other reagents. Because the acidic (or neutral) workup almost certainly leads to further reactions of the aldehyde (from H202 or other species generated from unreacted 02--), the product analysis
/
!01:3
/ January 31, 1979
also was performed for the reaction with excess C6H5CHO (K02/CE/C6H&HO = 1/1/3) in pyridine. In two runs the isolated products in toto accounted for 89 and 82%, respectively, of the original aldehyde. Relative to the reacted aldehyde, gas chromatographic analysis indicated yields of 17 and 5% C ~ H S C H ~ Orespectively; H, the isolated yields of benzoic acid were 3 1 and 44%, respectively. There were no traces of any other product, and in control runs for the extraction and recrystallization of benzoic acid we achieved variable 65-8570 recoveries (at best) for these small-scale complex mixtures (pyridine, acidic water, crown ether, benzene extractions). On the basis of our longer time runs with excess KO2, we conclude that benzoic acid is the ultimate end product of the reaction, but that benzyl alcohol is formed and slowly reacts further as described above. Benzaldehyde in Acetonitrile. Much of the preliminary work involved acetonitrile as the solvent. After a considerable amount of experimentation, the major products of the reaction of K02/CE with benzaldehyde in acetonitrile have been found to be cinnamonitrile (C&.jCH=CHCN, cis and trans) and benzoylacetonitrile (C6HsCOCH2CN) along with benzoic acid and small amounts of benzyl alcohol. The relative yields of these products depend upon the C ~ H S C H O / ratio K ~ ~and, perhaps, on some as yet undetermined variables. As in pyridine as solvent, benzaldehyde does not undergo an elementary reaction with 02-., but it does with 0 2 - - decomposition products and with acetonitrile anion (see Discussion section). Examples of yields based upon initial CsHsCHO are 5% cis-cinnamonitrile, 60% trans-cinnamonitrile, and 30% benzoylacetonitrile in a run with high KO2 (C6HsCHO/CE/KO> equal to 1/0.1/2); 16% unreacted C~HSCHO, 3% trans-cinnamonitrile, 35% benzoylacetonitrile, and 25% benzoic acid in a run with excess aldehyde (C6H5CHO/CE/K02 equal to 3/ l / l ) . When 0.13 g (2.4 mmol) of K O H is added to 0.12 mL (1.2 mmol) of C ~ H S C H O and 0.032 g (0.12 mmol) of C E in 2 m L of CH$N, a 76% yield (based upon starting C6H5C130) of cis- and trans-cinnamonitrile is obtained within 1 min. Cinnamonitrile is stable under the reaction conditions [0.032 g (0.12 mmol) of CE, 0.17 g (2.4 mmol) of KO2 in 2 m L of pyridine] but benzoylacetonitrile is not. From another control experiment, cinnamonitrile appears to be unstable in C E / CH3CN in the presence of basic H202(aq).
Discussion Esters. The present results confirm that esters undergo a primary reaction with 02--, while aromatic aldehydes and typical ketones do not. That esters are hydrolyzed to carboxylic acids and alcohols by 0 2 - - has been reported p r e v i ~ u s l y ; ~ ~ , ' ~ the data of Table I provide convincing evidence that this is an elementary reaction, The pathway presented in eq 1-6 is a slightly modified version of that proposed by Magno and Bontempellil6 for their study of electrochemically generated 0 2 - . in the presence of esters. Various other possibilities for steps subsequent to eq 2 were considered by those authors, but the electrochemical stoichiometry and the observation of an easily reduced transient ( d i a q l peroxide) led them to favor eq 3-5. San Fillip0 and co-workers14have shown that acyl-oxygen scission occurs and that the approximate order of reactivity for different n-octanoate esters follows typical ester acyl-oxygen cases. They also obtained evidence that reaction of diacyl peroxide with KO2 leads to carboxylic acid (reaction 6).22 The second-order rate constants for the reaction of 0 2 - . in pyridine with the two acetate esters in the present study are 1.1 X ( C H ~ C O ~ C ~ Hand S ) 1.6 X IO2 M-' s-l (CH3C02C6H5). This IO4 ratio of rates a t first seems surprising, but upon closer examination it is, in fact, consistent with other data for ethyl vs. phenyl esters in reactions with effective nucleophiles, as will be addressed n0w.23324
Gibian, Sawyer, et al.
/
0
II
RCOR’
+ 02-.
0
II
0
RCOO-
+ 0
I1
0
RCOOCR
-
0
II
RCOO.
-
0
RCOR’
I1 1I
643
Reactivity of Superoxide Ion with Carbonyl Compounds
+
R’O-
0
I I1 RCOOCR +
+ 2e-
(2)
R’O-
(4)
0
I
2RCO-
(5)
or
If eq 2 occurs via the usual nucleophilic attack at carbonyl, it can be expanded in eq 7 and 8, both being reversible. This
other hand, if benzaldehyde is added to a largely decomposed solution of superoxide ion in pyridine, then an accelerated decomposition of the remaining superoxide occurs. In accord with this result, when benzaldehyde is allowed to stand in the presence of 02-. for 0.5 h or more, the products of an apparent attack upon aldehyde are observed. Our conclusion is that the decomposition products of 0 2 - - are highly reactive toward benzaldehyde, with almost no fundamental reactivity between the original reagents. The subject of the aldehyde decomposition products will be addressed later, but first the lack of reactivity between 0 2 - a and benzaldehyde needs to be considered. As discussed in the previous section, there is an elementary reaction of 0 2 - - with esters; the carbonyl group of aldehydes and ketones should be at least as reactive toward the addition reaction. We believe that it is, but that the tetrahedral adduct does not undergo chemistry that is competitive with the reversal of the original addition (k-7). That this is realistic is supported by the relative rates for the ethyl and phenyl esters (Table I), in which k-7 must be dominant for the poorer leaving ethoxide case. For aldehydes and ketones the absence of a viable leaving group precludes elimination as a productive mode, so that the original addition must entirely reverse. An alternative to reactions 7, 8, and 3 (the hydrolysis pathway) is an electron transfer from superoxide ion to the peroxy radical generated in the addition step (i.e., eq 9 rather
I
00.
60.
followed by reaction 3
is a situation in which ks will be highly dependent upon the acidity of R’OH (Le., the stability of R’O-), and the ratelimiting step will depend upon the competition between k-7 and kg. For poor leaving groups k8 will be slow and rate limiting, but for good leaving groups k8 will be much more rapid, causing it to be competitive with k-7. In the present case, there are tetrahedral intermediates in which R’ is C6H5 or C2H5. The situation here is much akin to that which obtains for the imidazole (pK, 7) catalyzed hydrolysis of acetate^.^^-^^ That process exhibits a similar lo4 difference’ between phenyl and ethyl esters, ascribed to a change in the rate-limiting step with imidazole as the nucleophile. In our case, the loss of C6H5O- in eq 8 can compete much more effectively with the loss of 0 2 - * (k-7) than can the corresponding loss of C2H5O- from the ethyl ester. In the Magno and Bontempelli work16 the second-order rate constants for 0 2 - - hydrolysis of phenyl benzoate and p-chlorophenyl benzoate in DMF are 3 (in good agreement with the value obtained here in pyridine) and 25 M-’ s-l, respectively. The large (almost tenfold) increase observed upon the substitution of a p-chloro group in the phenolic moiety is again in accord with the mechanism of eq 7 and 8 (and is like that seen for imidazole attackon acetates, but not for attack by a strong base like OH-).23,24 Aldehydes. The electrochemical data clearly indicate that 0 2 - - does not undergo an elementary reaction with benzaldehyde. The rate of 0 2 - * disappearance in pyridine is unaffected by relatively high concentrations of pure benzaldehyde for at least 1 half-life of the superoxide. Impure aldehyde, however, causes a rapid 0 2 - - loss which is then followed by loss of aldehyde. In our view, this is due to proton-catalyzed 0 2 - decomposition 2 s the result of a benzoic acid impurity. On the
-
00-
than eq 8 after eq 7), and then decomposition of the dianionic tetrahedral intermediate.14 This bimolecular reaction of two anions would be expected to be slow and apparently cannot compete with the reversal of the addition or loss of X- (k-7 and kg), on the basis of the experimental results. If it did, not only would aldehydes and ketones react, but the reaction of ethyl and phenyl esters would be equally rapid in terms of the rate of 0 2 - - disappearance. Although the reduced intermediate
Y
